Encouraging SOLAR-1 Trial Results Lead to Alpelisib Approval

Since the 1980s,widely applied predictive markers in breast cancer have been limited to HER2 and hormone receptor (HR) status. That changed with the approval of alpelisib (Piqray), an inhibitor specific to PIK3CA, the alpha subunit of phosphatidylinositol 3-kinase (PI3K), by the FDA on May 24, 2019.¹The approval was based on the phase III SOLAR-1 trial that investigated postmenopausal women, as well as men, with HR-positive, HER2-negative, advanced breast cancer following progression on or after an endocrine-based regimen. The trial included patients both with and without PIK3CAmutations. The SOLAR-1 findings were presented during a satellite symposium at the 2019 European Society for Medical Oncology Breast Cancer Annual Congress in Berlin, Germany.²The trial demonstrated the role ofPIK3CAas a predictive marker for alpelisib’s clinical efficacy, said Peter A. Fasching, MD, associate professor of gynecology and obstetrics at Friedrich- Alexander University of Erlangen- Nuremberg in Germany, during the symposium. A number of PI3K inhibitors are in development (TABLE).²

“We have been [disadvantaged] with [just] 2 predictive markers to date,” Fasching said. “[Since the 1980s,] there has been no new clinically relevant marker that could predict treatment success.” The PI3K pathway is central in breast cancer and contributes to many physiological processes in other organs, such as the brain and liver. Alterations in the pathway and the resulting hyperactivation can contribute to the rise of malignancy and resistance to endocrine therapy.3-5 SOLAR-1 represents an opportunity “to see if the PI3Kmutation, which activates the pathway, could be a predictor of a therapy that inhibits the pathway,” Fasching said.⁴The investigators identifiedPIK3CAstatus in 572 patients with an ECOG performance status of ≤1. Patients withPIK3CA-mutant status (n = 341) were randomized to receive alpelisib (300 mg) plus fulvestrant (500 mg; Faslodex) versus placebo plus fulvestrant, and patients withPIK3CA-nonmutant status (n = 231) were randomized to receive alpelisib (300 mg) plus fulvestrant (500 mg) versus placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS) in thePIK3CA-mutant cohort, and the secondary endpoints included overall survival (OS) in both cohorts.⁶

In addition, patients were stratified 1:1 by the presence of liver or lung metastases and prior CDK4/6 inhibitor treatment. About half of the patients in each arm (alpelisib or placebo) had lung or liver metastases, and approximately 6% had received prior CDK4/6 therapy. “This is an important characteristic for physicians as they develop their treatment algorithms,” Fasching said. “Because CDK4/6 inhibitor treatment is a standard now, we will have to determine if alpelisib is effective after CDK4/6 therapy. These are factors to consider when treating our patients sequentially to continue the treatment of HR—positive patients in overcoming resistance.”

Among the subset of patients withPIK3CAmutations, the median PFS by local assessment was 11.0 months (95% CI, 7.5-14.5) for those who received the alpelisib combination compared with 5.7 months (95% CI, 3.7-7.4) for those who received placebo plus fulvestrant. Those results, assessed after a median follow-up of 20 months, translated to a 35% reduction in the risk of progression or death, with a hazard ratio of 0.65 in favor of alpelisib (95% CI, 0.50-0.85;P= .00065). There was no significant benefit of alpelisib for median PFS in patients without aPIK3CAmutation.

Among patients with thePIK3CAmutation, 93 (55.0%) in the alpelisib arm and 100 (58.1%) in the placebo arm had visceral disease. Among patients withPIK3CA-nonmutant status, 66 (57.4%) in the alpelisib arm and 74 (63.8%) in the placebo arm had visceral disease.

When looking at PFS across subgroups in the trial, Fasching noted a consistent pattern in which no subgroups were large enough to exclude a benefit of PIK3CA pathway inhibition in patients treated with alpelisib.

The overall response rate (ORR) in thePIK3CA-mutant cohort was 26.6% in the alpelisib plus fulvestrant arm compared with 12.8% in the placebo plus fulvestrant arm (P= .0006). Among patients with the mutation who had measurable disease, the ORRs were 36% and 16%, respectively (P= .0002).

For the entire study population, the rate of grade ≥3 adverse events (AEs) was 76.1% in the alpelisib plus fulvestrant arm compared with 35.5% in the placebo plus fulvestrant arm. Grade ≥3 hyperglycemia occurred in 36.6% of patients receiving alpelisib versus 0.7% receiving placebo. Dose interruptions due to hyperglycemia AEs occurred in 40.6% of patients and dose adjustments in 43.9%, said Fasching. Treatment discontinuation due to hyperglycemia AEs occurred in 6.3% of patients treated with alpelisib plus fulvestrant. “With regard to hyperglycemia, some clinicians may have to implement interdisciplinary approaches,” Fasching said. “In the study, treatment interruptions and treatment dose reductions along with metformin were the primary treatment modes to manage diabetes.”

Grade ≥3 rash, except maculopapular rash, developed in 9.9% of patients randomized to alpelisib and 0.3% randomized to placebo. The discontinuation rate of alpelisib plus fulvestrant due to AEs was 5% versus 1% for fulvestrant alone.

The advantage of usingPIK3CAas a predictive marker is that it “can identify patients who do not benefit from the treatment and maximize the effect in a population that does benefit from alpelisib,” Fasching concluded.

References

1. FDA approves alpelisib for metastatic breast cancer. US Food and Drug Administration website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer. Updated May 28, 2019. Accessed June 10, 2019.
2. Fasching PA. The advancing role of PI3K inhibitors—industry satellite symposium: innovation in HR+, HER2-advanced breast cancer and the emerging role of biomarkers. Presented at: European Society for Medical Oncology Breast Cancer 2019 Annual Congress; May 2-4, 2019; Berlin, Germany.
3. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer.J Clin Oncol. 2011;29(33):4452-4461. doi: 10.1200/JCO.2010.34.4879.
4. Saal LH, Johansson P, Holm K, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity.Proc Natl Acad Sci U S A. 2007;104(18):7564-7569. 10.1073/pnas.0702507104.
5. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways.Pharmgenomics Pers Med. 2014;7:203-215. doi: 10.2147/PGPM.S52762.
6. André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial.Ann Oncol. 2018;29(suppl 8; abstr LBA3_PR). academic.oup.com/annonc/article/29/suppl_8/mdy424.010/5141523
7. Janku F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients.Cancer Treat Rev. 2017;59:93-101. doi: 10.1016/j.ctrv.2017.07.005.
8. To Evaluate the Safety, Tolerability, and Pharmacokinetics of GDC-0077 Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer clinicaltrials.gov/ct2/show/NCT03006172?term=NCT03006172&rank=1. Updated June 5, 2019. Accessed June 10, 2019.